In vitro-in vivo extrapolation predicts drug-drug interactions arising from inhibition of codeine glucuronidation by dextropropoxyphene, fluconazole, ketoconazole, and methadone in humans.
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Raungrut P, Uchaipichat V, Elliot DJ, Janchawee B, Somogyi AA, Miners JO
In vitro-in vivo extrapolation predicts drug-drug interactions arising from inhibition of codeine glucuronidation by dextropropoxyphene, fluconazole, ketoconazole, and methadone in humans.
J Pharmacol Exp Ther. 2010 Aug;334(2):609-18. doi: 10.1124/jpet.110.167916. Epub 2010 May 18.
- PubMed ID
- 20484152 [ View in PubMed]
- Abstract
Because codeine (COD) is eliminated primarily via glucuronidation, factors that alter COD glucuronide formation potentially affect the proportion of the dose converted to the pharmacologically active metabolite morphine. Thus, in vitro-in vivo extrapolation approaches were used to identify potential drug-drug interactions arising from inhibition of COD glucuronidation in humans. Initial studies characterized the kinetics of COD-6-glucuronide (C6G) formation by human liver microsomes (HLM) and demonstrated an 88% reduction in the Michaelis constant (K(m)) (0.29 versus 2.32 mM) for incubations performed in the presence of 2% bovine serum albumin (BSA). Of 13 recombinant UDP-glucuronosyltransferase (UGT) enzymes screened for COD glucuronidation activity, only UGT2B4 and UGT2B7 exhibited activity. The respective S(50) values (0.32 and 0.27 mM) generated in the presence of BSA were comparable with the mean K(m) observed in HLM. Known inhibitors of UGT2B7 activity in vitro or in vivo and drugs marketed as compound formulations with COD were investigated for inhibition of C6G formation by HLM. Inhibition screening identified potential interactions with dextropropoxyphene, fluconazole, ketoconazole, and methadone. Inhibitor constant values generated for dextropropoxyphene (3.5 microM), fluconazole (202 microM), ketoconazole (0.66 microM), and methadone (0.32 microM) predicted 1.60- to 3.66-fold increases in the area under the drug plasma concentration-time curve ratio for COD in vivo. Whereas fluconazole and ketoconazole inhibited UGT2B4- and UGT2B7-catalyzed COD glucuronidation to a similar extent, inhibition by dextropropoxyphene and methadone resulted largely from an effect on UGT2B4. Interactions with dextropropoxyphene, fluconazole, ketoconazole, and methadone potentially affect the intensity and duration of COD analgesia.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Codeine UDP-glucuronosyltransferase 2B4 Protein Humans UnknownSubstrateDetails Codeine UDP-glucuronosyltransferase 2B7 Protein Humans UnknownSubstrateDetails Dextropropoxyphene UDP-glucuronosyltransferase 2B4 Protein Humans UnknownInhibitorDetails Methadone UDP-glucuronosyltransferase 2B4 Protein Humans NoInhibitorDetails